Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC).

Abstract

9009 Background: Most patients (pts) with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) NSCLC develop resistance to tyrosine kinase inhibitor (TKI) therapy, with the central nervous system (CNS) as a common site of relapse. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI active against most known resistance mutations. Methods: In Ph. I of the ongoing Ph. I/II study NCT01970865, eligible pts had ALK+ or ROS1+ NSCLC with/without brain metastases (mets) and were treatment naïve or had disease progression after ≥1 TKIs. Pts received lorlatinib on day –7 and daily from day 1. Primary objective was to identify the MTD and recommended Ph. II dose (RP2D). Other objectives were safety and efficacy by RECIST v1.1, including intracranial activity. Results: Of 54 pts treated in Ph. I as of Nov 30 2015, 41 were ALK+, 12 ROS1+; and 1 with mutation status not recorded at cut-off date. Pts were heavily pretreated:27 had received >1 prior TKI, 20 1 prior TKI and 7 were TKI naïve; 39 pts had CNS mets at baseline. Pts were treated across 10 dose levels (10–200 mg). Response rates (RR) are shown in the Table. 29 pts remain on treatment. The most common treatment-related adverse events (AEs) were hypercholesterolemia (54%) and peripheral edema (37%). Hypercholesterolemia was the most common (9%) grade (G) ≥3 treatment-related AE and most frequent reason for dose delay/reduction. No pt discontinued due to a treatment-related AE. One DLT occurred in a pt who received <16/21 planned 200 mg daily doses due to G2 CNS AEs. CSF concentrations in steady-state samples from 3 pts with CNS mets showed excellent penetration of lorlatinib into the CNS. Conclusions: Lorlatinib was well tolerated and demonstrated durable clinical responses, including intracranial responses, in ALK+ (including G1202R+) pts and ROS1+ NSCLC pts, many of whom had CNS mets and ≥1 prior TKIs. The RP2D was identified as 100 mg once daily. Ph. II is enrolling. Clinical trial information: NCT01970865. N CR uCR PR uPR Overall RR n (%) Intracranial (IC) + extracranial 52 2 (4) 1 (2) 22 (42) 1 (2) 26 (50) IC (target + nontarget lesions) 36 8 (22) 2 (6) 4 (11) 2 (6) 16 (44) IC (target lesions) 20 5 (25) 1 (5) 4 (20) 2 (10) 12 (60) Abbreviations: CR, complete response; PR, partial response; U, unconfirmed.